The development of strategies for the transfer of genes into desired cells offers new therapeutic possibilities. For example, several methods for in vivo gene transfer to the vascular wall have been explored, including reimplantation of vascular cells which have been genetically engineered in vitro (Nabel, et al., Science, Vol. 244, pgs. 1342-1344 (1989); Wilson, et al., Science, Vol. 244, pgs. 1344-1346 (1989); Dichek, et al., Circulation, Vol. 80, pgs. 1347-1353 (1989)) as well as direct, in vivo gene transfer using several types of gene delivery vehicles, including plasmid DNA complexes (LeClerc, et al., J.Clin.Invest., Vol. 90, pgs. 936-944 (1992) Nabel, et al., Science, Vol. 249, pgs. 1285-1288 (1991); retroviral vectors (Nabel, et al., 1990, Flugelman, et al.,, Circulation, Vol. 85, pgs. 1110-1117 (1992)); Lim, et al., Circulation, Vol. 83, pgs. 2007-2011 (1991)), retroviral vectors (Nabel, et al., 1990; Flugelman, et al., Circulation, Vol. 85, pgs. 1110-1117 (1992)) and adenoviral vectors (Guzman, et al., Circulation, Vol. 88, pgs. 2838-2848 (1993); Lemarchand, et al., Proc. Nat. Acad. Sci., Vol. 89, pgs. 6482-6486 (1992); Lee, et al., Circ. Res., Vol. 73, pgs. 797-807 (1993)). In this context, the blood flow constantly dilutes the local milieu of the vessel wall at a rapid rate as compared with the finite time required for vector binding and gene transfer into cells, and several features of gene transfer to the vascular wall have been hypothesized. First, delivery of genes to specific regions of a vessel may require physical localization of vector during uptake into the vessel wall segment. Catheter-based strategies employing a variety of catheter designs are being explored for this purpose. (March, et al., Cardio Intervention, Vol. 2, No. 2, pgs. 11-26 (1992)). Several studies have reported successes using a dual ligature or dual-balloon approach to isolate a section of the vascular wall during transduction. (LeClerc, et al., J.Clin.Invest., Vol. 90, pgs. 936-944 (1992); Nabel, et al., 1990; Lim, et al., 1991; Flugelman, et al., 1992; Lemarchand, et al., 1992; Lee, et al., 1993; Guzman, et al., 1993). Second, to the extent that localization of gene delivery to a specific region is important, maximization of specific vascular gene delivery must be accomplished. Third, the time permitted for gene transfer will be limited by pathologic alterations imposed by gene transfer; i.e., potential ischemia in the vascular distribution distal to a segmental isolation. The rate of gene transfer into vascular wall cells must be sufficiently rapid to achieve an adequate absolute level of transduction in the available time.
Gene delivery vehicles which may be employed include retroviral vectors and adenoviral vectors. Retroviral vectors may be employed for infecting dividing cells, while adenoviral vectors may be employed for infecting dividing and non-dividing cells. Adenoviral vectors have been used successfully for in vivo gene transfer of marker genes such as .beta.-galactosidase (Stratford-Perricaudet, et al., Hum. Gene Ther. Vol. 1, pgs. 240-256 (1990); Mastrangeli, et al., J. Clin, Invest., Vol. 91, pgs. 225-234 (1993); Englehart, et al., Nat. Genet., Vol. 4, pgs. 27-34 (1993); Yei, et al. Hum. Gene Ther., Vol. 5, pgs. 733-746 (1994)), the luciferase gene (Trapnell, Adv. Drug. Del. Rev., Vol. 12, pgs. 185-199 (1994)), as well as potentially therapeutic genes such as ornithine transcarbamylase (Stratford-Perricaudet, et al., 1990), .alpha.-1-antitrypsin (Rosenfeld, et al., Science, Vol. 252, pgs. 431-434 (1991)), cystic fibrosis transmembrane conductance regulator, (Rosenfeld, et al., Cell, Vol. 68, pgs. 143-155 (1992); Dabner, et al., Nature Genet., Vol. 1, pgs. 75-83 (1993)); Factor IX (Smith, et al., Nature Genet., Vol. 5, pgs. 397-402 (1993)), dystrophin (Vincent, et al., Nat. Genet., Vol. 5, pgs. 130-134 (1993)) and chimeric inhibitors of tumor necrosis factor (Kolls, et al., Proc. Nat. Acad. Sci., Vol. 91, pgs. 215-219 (1994)), to a variety of organs and tissues. Initial studies of adenoviral gene transfer into the vascular wall (Lemarchand, et al., 1992; Lee, et al., 1993; Guzman, et al., 1993) have demonstrated substantially higher transduction frequency than observed using similar protocols with plasmid/liposome complexes or retroviruses. Gene delivery in these studies was accomplished only with isolation of the vascular segment to be transduced for 20 to 45 minutes to permit sufficient vector uptake.